Synthesis of Novel (Aryloxy)propanolamines and Related Compounds Possessing Both Class II and Class III Antiarrhythmic Activity

J Med Chem. 1990 Oct;33(10):2883-91. doi: 10.1021/jm00172a033.

Abstract

Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.

MeSH terms

  • Action Potentials / drug effects
  • Adrenergic beta-Antagonists / chemical synthesis*
  • Adrenergic beta-Antagonists / metabolism
  • Animals
  • Anti-Arrhythmia Agents / chemical synthesis*
  • Anti-Arrhythmia Agents / metabolism
  • Blood Pressure / drug effects
  • Chemical Phenomena
  • Chemistry, Physical
  • Dogs
  • Drug Design
  • Epinephrine / antagonists & inhibitors
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Propanolamines / chemical synthesis*
  • Propanolamines / metabolism
  • Purkinje Fibers / physiology
  • Receptors, Adrenergic, beta / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • Propanolamines
  • Receptors, Adrenergic, beta
  • Epinephrine